The airway smooth muscle cell: a major contributor to asthma?
The airway smooth muscle cell: a major contributor to asthma?
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DOI：
10.1034/j.1399-3003.2000.15.02.x
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发表时间：
2000-03
期刊：
影响因子：
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通讯作者：
K. Chung;P. Sterk
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文献类型：
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作者：
K. Chung;P. Sterk
自1822年REISSEISEN [1]首次描述了从中央气道延伸至膜性细支气管水平的支气管树的气道平滑肌（ASM）以来，对气道的这一重要组成部分在健康和疾病中的生理功能的忽视一直存在。总有一天，当开发出一种没有ASM的航空模型时，上述问题肯定会得到回答。奇怪的是，似乎很明显，在疾病状态下，如哮喘，ASM在很大程度上有助于气道管腔狭窄，因此，气道阻塞的发展。因此，这并不奇怪，许多工作已经针对阐明ASM的收缩事件的生理学，生物化学和药理学。生物学家还关注哮喘中是否存在ASM的任何基本异常[2]，这些异常可以解释支气管高反应性的非常典型的特征，通常在哮喘中观察到，有时在慢性阻塞性肺疾病中观察到。这种支气管高反应性包括体内对支气管收缩刺激的敏感性和最大反应的增加[3]。在20世纪80年代后期，未能观察到体内高反应性和体外ASM收缩性之间的任何关系[4]，严重削弱了ASM在疾病中的作用。然而，这些实验几乎完全是在非哮喘患者中进行的，因为恶性肿瘤可以获得肺切除材料。在可获得致死性哮喘患者组织的少数情况下，似乎ASM在体外确实显示出异常，如最大收缩力增加和舒张反应受损[5]。ASM参与哮喘等疾病的可能性有多种：继发于气道弹性降低或气道/实质相互依赖性改变的平滑肌过度缩短，ASM过量导致产生更多的力，或收缩速度过快[6]。在该杂志的先前综述中，FREDBERG [7]强调了平滑肌行为本身动力学（跨桥循环速率和细胞可塑性）及其与其直接环境的机械耦合的微妙平衡的重要性。当然，发现ASM的基本异常是哮喘的圣杯的一部分，它是疾病中支气管高反应性的原因。一个明确的目标，但现在要解决的！在因哮喘持续状态死亡的患者的尸检标本中，ASM体积增加的描述是关于ASM在疾病中的作用和贡献的新观点发展的另一个里程碑[8]。当然，这导致了更多关于ASM增殖行为的最新研究，提供了关于ASM增殖介质及其亚细胞机制的大量信息，至少在体外[9]。但是，ASM如何在体内增殖？最后，尽管我们已经习惯了ASM细胞主要受到从其他邻近结构或炎症细胞释放的介质的影响的想法，但最近的工作表明这些细胞在产生广泛的促炎细胞因子方面的多效性[10]。因此，这是一种可收缩的组织，可以增殖并被诱导释放细胞因子/介质。这些收缩、分泌和增殖的“表型”在特定条件下同时共存于同一肌肉细胞中，还是这些细胞受炎症环境的影响而交替出现？此外，这些表型是如何相互影响的，特别是在收缩反应方面？因此，最新的观察创造了有吸引力的假设，参与ASM哮喘。鉴于ASM的生理学、生物化学、病理学和药理学方面的新信息激增，2000年，本杂志将对不断发展的想法和新发现进行一系列简短的评论。这一系列的文章来自于1998年瑞士日内瓦ERS大会上的“气道平滑肌”专题讨论会。该系列将从美国印第安纳州印第安纳波利斯的GUNST和TANG [11]的贡献开始，讨论ASM的收缩装置和机械特性。然后，来自澳大利亚珀斯的JAMES和卡罗尔[12]将关注疾病中ASM的结构变化。来自英国伦敦的CHUNG [13]将专注于ASM与气道炎症相关的分泌方面。HIRST等人[14]将综述ASM的表型多样性和增殖变化。随后，来自加拿大蒙特利尔的MARTIN等人[15]将讨论ASM对气道狭窄和支气管高反应性的贡献。来自英国诺丁汉的HALL [16]将指导读者了解ASM的第二信使、离子通道和基本药理学。* 英国伦敦帝国学院医学院国家心肺研究所。** 荷兰莱顿大学医学中心肺病科。
Since REISSEISEN [1] first described the airway smooth muscle (ASM) of the bronchial tree extending from the central airways to the level of the membranous bronchiole in 1822, ignorance of the physiological function of this prominent component of the airways in health and disease has continued. The above question will surely be answered one day, when a model of conducting airways devoid of ASM is developed. Paradoxically, it seems clear that under disease states, such as asthma, ASM contributes to a large extent to airway luminal narrowing and, therefore, to the development of airways obstruction. Therefore, it does not come as a surprise that much work has been targeted towards elucidating the physiology, biochemistry and pharmacology of the contractile events of ASM. Biologists have also been concerned with whether there are any fundamental abnormalities of ASM in asthma [2] that could account for the very characteristic feature of bronchial hyperresponsiveness, commonly observed in asthma and sometimes in chronic obstructive pulmonary disease. Such bronchial hyperresponsiveness includes an increase in sensitivity as well as in maximal response to bronchoconstrictor stimuli in vivo [3]. The failure to observe any relationship between these features of hyperresponsiveness in vivo and ASM contractility in vitro during the late 1980s [4] seriously weakened the case for a role for ASM in disease. However, these experiments were almost exclusively performed in nonasthmatics in whom lung resection material could be obtained because of malignancies. In the few instances in which tissue from patients with fatal asthma was available, it appeared that ASM did show abnormalities in vitro, such as increased maximal contractility and impaired relaxant responses [5]. There are various possibilities for the involvement of ASM in diseases such as asthma: excessive smooth muscle shortening secondary to decreased airway elastance or altered airway/parenchymal interdependence, an excessive amount of ASM causing more force generation, or an excessive velocity of contraction [6]. In a previous review in this Journal, FREDBERG [7] emphasized the importance of the delicate equilibrium of the dynamics of smooth muscle behaviour itself (cross-bridge cycling rate and cellular plasticity) and of its mechanical coupling to its direct environment. Certainly, finding out about the fundamental abnormality of ASM that accounts for the bronchial hyperresponsiveness in disease forms part of the Holy Grail of asthma. A clear objective, but one that is now to be solved! The description of increased ASM bulk in the autopsy specimens of patients who have died because of status asthmaticus has been another milestone in the development of new ideas about the role and contribution of ASM in disease [8]. Certainly, this led to more recent studies on the proliferative behaviour of ASM, providing considerable information concerning the mediators of ASM proliferation and the subcellular mechanisms thereof, at least in vitro [9]. But, how does ASM proliferate in vivo? Finally, although we have been accustomed to the idea that the ASM cell is mainly subject to the effects of mediators released from other neighbouring structural or inflammatory cells, more recent work indicates the pleotropic nature of these cells in producing a wide range of pro-inflammatory cytokines [10]. Therefore, this is a contractile tissue that can proliferate and be induced to release cytokines/mediators. Do these contractile, secretory and proliferative "phenotypes" coexist in the same muscle cell at the same time under certain conditions or do these cells alternate, influenced by the inflammatory milieu? Also, how do these phenotypes impinge on each other, particularly with regard to the contractile response? Thus, the most recent observations have created attractive hypotheses on the involvement of ASM in asthma. In view of the explosion of new information on the physiology, biochemistry, pathology and pharmacology of ASM, in the year 2000, this Journal will be running a short series of reviews on the evolving ideas and novel findings. This series arose from a symposium on "The airway smooth muscle" at the 1998 ERS Congress in Geneva, Switzerland. The series will start with a contribution by GUNST and TANG [11] from Indianapolis, IN, USA, addressing the contractile apparatus and mechanical properties of ASM. Then, JAMES and CARROLL [12], from Perth, Australia, will focus on the structural changes of ASM in disease. CHUNG [13], from London, UK, will focus on the secretory aspects of ASM in relation to airways inflammation. HIRST et al. [14] will review the phenotypic diversity and proliferative changes in ASM. Subsequently, MARTIN et al. [15], from Montreal, Canada, will discuss the contribution of ASM to airway narrowing and bronchial hyperresponsiveness. HALL [16], from Nottingham, UK, will guide the reader through the second messengers, ion channels and basic pharmacology of ASM. *National Heart & Lung Institute, Imperial College School of Medicine, London, UK. **Dept of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.